Mounting evidence suggests that stress and the major stress hormone, corticosterone, induce divergent and profound influences in the brain, with acute stress triggering responses that are essential for adaptation and maintenance of homeostasis and chronic stress producing maladaptive changes that lead to cognitive and emotional disturbances. In this application, we will use combined electrophysiological, biochemical, immunocytochemical, molecular and behavioral approaches to address 3 specific aims: (1) To examine the synaptic targets for the complex effects of stress. We will determine whether glutamate receptors (NMDARs and AMPARs) in prefrontal cortex (PFC) are key targets at synapses that are differentially regulated by different kinds of stress, which is causally linke to their complex effects on PFC-dependent cognitive functions. (2) To identify the determining factor for the switch from the positive effects of acute stress to the negative effects of repeated stress. We will determine whether the transition is attributable to the loss of key signaling molecules (e.g. Serum- and Glucocorticoid-Inducible Kinase) and synaptic proteins (e.g. AMPAR GluR1 subunit) by upregulated E3 ubiquitin ligase Nedd4 in response to prolonged glucocorticoid receptor activation. (3) To explore novel strategies to rescue the detrimental effects of chronic stress. Altered histone acetylation and transcriptional dysfunction have been implicated in a wide range of neurologic and psychiatric disorders. Our recent studies have found that HDAC2 is upregulated in PFC of repeatedly stressed animals, which is responsible for the transcriptional modification of Nedd4. We will examine whether HDAC2 inhibition is a potential therapeutic strategy to rescue the deleterious effects of chronic stress on synaptic and cognitive function. This proposal will address important issues on the molecular mechanisms underlying the complex actions of stress hormones. Results gained from study will reveal how the corticosteroid-glutamate interactions contribute to cognitive functions in normal states and stress-related mental illnesses. Our studies will also provide valuable targets for designing novel therapies to modify the stress responses.